The primary goal of this project is to apply sophisticated in vivo imaging, biochemical, and neuropathological techniques to mouse models of Parkinson's Disease in order to test our central hypothesis listed below. The long-term goal of the candidate is to run an independent research group focused on understanding how neurodegeneration occurs in Parkinson's disease and to practice medicine as a movement disorders specialist. The proposed work will be carried out in the Neurology Department at Massachusetts General Hospital (MGH), in the laboratory of Dr. Bradley Hyman, an established leader in neurodegeneration research with an excellent track record of mentoring young physician-scientists. Proteins can exist in the cell in a number of aggregated states, some of which are thought to produce the toxic effects that give rise to many neurodegenerative diseases. Our central hypothesis is that neurons in the living brain use different specific mechanisms for clearing protein aggregates of varying sizes from the cell. By combining in vivo multiphoton imaging, biochemical, and neuropathological techniques with pharmacological approaches, the candidate will test 3 specific hypotheses related to how the abnormal metabolism of the protein 1-synuclein may lead to Parkinson's Disease and related disorders: Hypothesis 1) An autophagic pathway degrades larger aggregate species of 1-synuclein. Hypothesis 2) The proteasome pathway degrades smaller aggregate species of 1-synuclein. Hypothesis 3) Impaired protein clearance leads to presynaptic 1-synuclein aggregation and synaptic degeneration. These investigations will help to characterize how levels of 1-synuclein protein are regulated by neurons; a better understanding of this regulation could to lead to new therapeutic strategies to treat Parkinson's Disease. In addition to providing time for basic disease-focused research, this proposal includes specific components directed towards helping the candidate transition into an independent physician-scientist career. These important components include structured mentoring by a leader in the field; specific coursework in the fields of neurodegeneration, statistics, biological imaging, and the responsible conduct of research; and time evaluating and treating patients with Parkinson's Disease and related disorders in the MGH Movement Disorders clinic. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to better understand what mechanisms lead to the death of brain cells in Parkinson's Disease and related disorders. It is hoped that this work will reveal some of the specific cellular pathways involved in neurodegeneration so that they can become targets for new drug development to treat these diseases.